Evaluation of the Pharmacological Profile of Ramosetron, a Novel Therapeutic Agent for Irritable Bowel Syndrome

Hirata, Tetsuya; Keto, Yoshihiro; Funatsu, Toshiyuki; Akuzawa, Shinobu; Sasamata, Masao

doi:10.1254/jphs.fp0070620

Cited by 38 publications

(35 citation statements)

References 31 publications

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“…Ramosetron is another 5-HT3RA, proven effective in IBS-D,35 but unfortunately only marketed in Japan. It has an affinity for the 5-HT3 receptor three times that of alosetron36 but is given at a very low dose of 5 μg, equivalent to 0.015 mg alosetron, again suggesting that lower doses of 5-HT3RAs might well be the best strategy in treating IBS-D.…”

Section: Discussionmentioning

confidence: 99%

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea

Garsed

Chernova

Hastings

et al. 2013

Gut

195

158

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BackgroundIrritable bowel syndrome with diarrhoea (IBS-D) is particularly debilitating due to urgency and episodic incontinence. Some 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (5-HT3RAs) have proven effective but have serious side effects. Ondansetron, also a 5-HT3RA, has been widely used as an antiemetic with an excellent safety record for over two decades. Our aim was to assess its effectiveness in IBS-D.Methods120 patients meeting Rome III criteria for IBS-D entered a randomised, double-blind, placebo-controlled crossover study of 5 weeks of ondansetron 4 mg versus placebo with dose titration allowed, up to two tablets three times daily in the first 3 weeks. Patients completed daily diaries documenting stool consistency using the Bristol Stool Form score. Gut transit was measured in the last week of each treatment. The primary endpoint was average stool consistency in the last 2 weeks of treatment.ResultsOndansetron significantly improved stool consistency (mean difference in stool form between ondansetron and placebo −0.9, 95% CI −1.1 to −0.6, p<0.001). Compared with placebo, patients on ondansetron experienced fewer days with urgency (p<0.001), lower urgency scores (p<0.001), reduced frequency of defaecation (p=0.002) and less bloating (p=0.002), although pain scores did not change significantly. IBS symptom severity score fell more with ondansetron than placebo (83±9.8 vs 37±9.7, p=0.001). 65% reported adequate relief with ondansetron but not placebo compared with 14% reporting relief with placebo but not ondansetron, relative risk 4.7, 95% CI 2.6 to 8.5, p<0.001.ConclusionsOndansetron relieves some of the most intrusive symptoms of IBS-D, namely loose stools, frequency and urgency.

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Section: Discussionmentioning

confidence: 99%

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea

Garsed

Chernova

Hastings

et al. 2013

Gut

195

158

View full text Add to dashboard Cite

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“…By extension the elevated levels of CRH mRNA in the central nucleus of the amygdala of 5-HT3A-R knockout mice may be an upstream compensation for a chronically depressed HPA-axis (Bhatnagar et al, 2004b), although it could also reflect a loss of normal GABAergic facilitation mediated by this receptor in the amygdala Turner et al, 2004). Systemic treatment with 5-HT3-R antagonists including ondansetron and ramosetron also inhibit CRH and restraint stress-induced colonic propulsion (Hirata et al, 2007;Miyata et al, 1993Miyata et al, , 1998Yamamoto et al, 1998). This is one reason why 5-HT3-R antagonists have garnered interest as potential treatments for Irritable Bowel Syndrome, a condition frequently found in stress-related conditions (Gershon, 2005).…”

Section: -Ht3 Receptorsmentioning

confidence: 96%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

249

166

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The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

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“…Preliminary pharmacokinetic data suggest that it has a greater affinity, slower dissociation, and stronger antagonism at the 5-HT3 receptor than either alosetron or cilansetron [54] . It also appears to be superior to both of these medications in inhibiting stress-induced defecation and stress-induced changes in colonic transit rates in rats [54,55] . Data in human use are not available but can be anticipated in the near future.…”

Section: -Ht3 Antagonistsmentioning

confidence: 99%

Updates on treatment of irritable bowel syndrome

Hammerle¹,

Surawicz²

2008

WJG

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Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder characterized by abdominal pain and discomfort in association with altered bowel habits. It is estimated to affect 10%-15% of the Western population, and has a large impact on quality of life and (in)direct healthcare costs. IBS is a multifactorial disorder involving dysregulation within the brain-gut axis, and it is frequently associated with gastrointestinal motor and sensory dysfunction, enteric and central nervous system irregularities, neuroimmune dysregulation, and postinfectious inflammation. As with other functional medical disorders, the treatment for IBS can be challenging. Conventional therapy for those with moderate to severe symptoms is largely unsatisfactory, and the development of new and effective drugs is made difficult by the complex pathogenesis, variety of symptoms, and lack of objective clinical findings that are the hallmark of this disorder. Fortunately, research advances over the past several decades have provided insight into potential mechanisms responsible for the pathogenesis of IBS, and have led to the development of several promising pharmaceutical agents. In recent years there has been much publicity over several of these new IBS medications (alosetron and tegaserod) because of their reported association with ischemic colitis and cardiovascular disease. While these agents remain available for use under restricted prescribing programs, this highlights the need for continued development of safe and effective medication for IBS. This article provides a physiologicallybased overview of recently developed and frequently employed pharmaceutical agents used to treat IBS, and discusses some non-pharmaceutical options that may be beneficial in this disorder.

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Evaluation of the Pharmacological Profile of Ramosetron, a Novel Therapeutic Agent for Irritable Bowel Syndrome

Cited by 38 publications

References 31 publications

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Updates on treatment of irritable bowel syndrome

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